What is the relationship between a microdose used in a Phase 0 and pharmacological dose PK?
Xceleron has examined 36 real development candidates in microdose studies in 20 different programs. In 12 of these programs, a candidate molecule was selected to develop further. All 12 of these candidates showed linear PK showing that for real drugs there is an excellent correlation between microdose and therapeutic dose PK.
Xceleron participated in a five compound Microdose study supported by the Consortium for Resourcing and Evaluating AMS Microdosing (CREAM) which was published in 2006. This EU-funded trial looked at the relationship between pharmacologic and microdose data.
What about drugs showing saturation pharmacokinetics or that are transporter substrates?
If you have a drug that may only work at high therapeutic doses which are saturating then microdosing may be unsuitable. Two transporter substrates (fexofenadine and clarithromycin) were examined in an EU-funded microdose to therapeutic dose comparative study (EUMAPP) and both showed a good correlation between microdose and pharmacological dosed PK.
Do I need GMP material to conduct a Phase 0 study?
You do not need GMP material for either the cold drug or the
14C-labeled drug in order to conduct a Phase 0 study. The recent FDA cGMP guidance specifies what is needed (
http://www.fda.gov/Cder/Guidance/GMP%20Phase1IND61608.pdf)
Why can’t I use LC/MS for microdose analysis?
You can but only for drugs that have a low volume of distribution and have high bioavailability. You could spend months developing a suitable LC/MS method whereas with AMS you can use the same procedures irrespective of the molecule. With AMS you will also get some metabolism information as well as renal clearance if you collect urine.
Can I obtain drug targeting information from a microdose study?
Provided you have access to the necessary cells, tissues or body fluids, the sensitivity of AMS will enable drug concentrations to be measured. Xceleron has successfully measured drugs in extravascular fluid, white blood cells, CSF, lung biopsies and BAL etc.
Do I need to conduct dosimetry work to support Phase 0 studies?
Xceleron has a number of preferred supplier clinics and have approved administration of up to 2 microCuries to human subjects without supporting dosimetry.
Can I conduct a Phase 0 study with a biologic candidate?
Phase 0 studies are not suitable to studying monoclonal or polyclonal antibodies owing to their high affinity binding to their target (all administered drug is bound and does not come off; there is no free drug). Microdosing may be suitable for proteins that are soluble eg cytokines, growth promoters etc.
What kinds of samples can be studied in a Microdose study?
Traditionally plasma is analyzed, and sometimes urine and feces.
Xceleron however has considerable experience in analyzing biopsy samples to determine drug distribution. Such samples include lung biopsy, alveolar macrophages, cerebral spinal fluid, skin and skin blister fluid.
Phase 0 Microdosing
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